Age-Dependent Estrogen-Independent Mechanism of Hyposomatotropism in Women

描述(由申请人提供)：R01 AG029362在绝经后妇女中的竞争性更新与正在进行的R37 AG019695(睾丸激素对衰老男性生长激素轴的作用)的重点平行。在绝经后的女性中，前哨问题是残留的内源性卵巢和肾上腺衍生雌激素在GH调节中的作用，以及雌二醇(E2)调节GH产生的下丘脑-垂体机制。内源性E2在GH调节中的作用将被用一种独特的性类固醇钳制范例来研究，该范例旨在抑制雄激素前体合成E2，并通过ER阻断E2的组织作用。将使用新的多肽选择性钳制范例来研究E2的作用机制，这些范例旨在揭示相互作用的多肽介导的途径，这些途径共同(在整体上)调节脉动性生长激素的分泌。脉动性生长激素分泌占每日生长激素总产量的85%。E2作用的显著物种差异使得临床研究对于理解机制是必不可少的。临床研究难度的增加反过来又要求应用更强大的分析技术。因此，目前的更新结合了(1)创新性类固醇钳；(2)信息性多肽特定的生长激素途径钳；以及(3)引人注目的新分析方法，以剖析迫使绝经后个体脉动性生长激素分泌下降的整体水平(多途径)机制。老年女性和男性GH分泌贫乏的重要意义在于，与低GH状态相关的腹内肥胖、胰岛素抵抗、血脂异常、心血管死亡、骨骼减少、骨量减少和身体虚弱的风险增加：预防或补救这些风险对于维持美国老年公民的健康至关重要。因此，目标是促进新的非类固醇和非肽基手段的发展，以防止与年龄相关的生长激素和胰岛素样生长因子-I合成代谢的减少。

DESCRIPTION (provided by applicant): This competitive renewal of R01 AG029362 in postmenopausal women parallels the focus of ongoing R37 AG019695 (Actions of Testosterone on the Aging Male GH Axis). In postmenopausal women, sentinel questions are the roles of residual endogenous ovarian and adrenal-derived estrogen in GH regulation, and the hypothalamo-pituitary mechanisms by which estradiol (E2) regulates GH production. The roles of endogenous E2 in GH regulation will be investigated using a unique sex-steroid clamp paradigm designed to inhibit E2 synthesis from androgen precursors, and block tissue actions of E2 via ER. The mechanisms of E2 action will be studied using novel peptide-selective clamp paradigms created to unmask interacting peptide-mediated pathways that jointly (in ensemble) regulate pulsatile GH secretion. Pulsatile GH secretion accounts for > 85% of total daily GH production. Prominent species differences in E2 action make clinical investigations essential for mechanistic understanding. The increased difficulty level of clinical studies in turn requires the application of more powerful analytical technology. Accordingly, the present renewal combines all three of (1) innovative sex-steroid clamps; (2) informative peptide-specific GH-pathway clamps; and (3) compelling new analytical methods to dissect ensemble-level (multipathway) mechanisms forcing the decline of pulsatile GH secretion in postmenopausal individuals. The significance of impoverished GH secretion in aging women and men is the increased risk of intra-abdominal obesity, insulin resistance, dyslipidemia, cardiovascular mortality, sarcopenia, osteopenia and physical frailty associated with the low-GH state: Prevention or remediation of these risks is central to maintaining the health of older U.S. citizens. The goal thereby is to promote the development of new non-steroidal and non-peptidyl means to forestall age-related decrements in GH and IGF-I drive to anabolism.